Coenzyme Q10 and Dementia: A Systematic Review

It is well known that coenzyme Q10 (CoQ10) has important antioxidant properties. Because one of the main mechanisms involved in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative diseases is oxidative stress, analysis of the concentrations of CoQ10 in different tissues of AD patients and with other dementia syndromes and the possible therapeutic role of CoQ10 in AD have been addressed in several studies. We performed a systematic review and a meta-analysis of these studies measuring tissue CoQ10 levels in patients with dementia and controls which showed that, compared with controls, AD patients had similar serum/plasma CoQ10 levels. We also revised the possible therapeutic effects of CoQ10 in experimental models of AD and other dementias (which showed important neuroprotective effects of coenzyme Q10) and in humans with AD, other dementias, and mild cognitive impairment (with inconclusive results). The potential role of CoQ10 treatment in AD and in improving memory in aged rodents shown in experimental models deserves future studies in patients with AD, other causes of dementia, and mild cognitive impairment.


Introduction
The 1,4-benzoquinone ubiquinone or coenzyme Q 10 (CoQ 10 ), which is present in the majority of tissues in the human body, is an important component of the mitochondrial electron transport, participating in the generation of cellular energy through oxidative phosphorylation, and can be present in tissues in three different redox states: fully reduced (ubiquinol), fully oxidized (ubiquinone), and partially oxidized (semiquinone or ubisemiquinone). In addition to mitochondria, CoQ 10 is present in peroxisomes, lysosomes, and the Golgi apparatus. CoQ 10 has important antioxidant properties, with both a direct antioxidant effect of scavenging free radicals, and an indirect one of participating in the regeneration of other antioxidants such as ascorbic acid and alpha-tocopherol, offering protection to cells against oxidative stress processes [1,2].
It is well known that one of the most important pathogenetic mechanisms of Alzheimer's disease (AD) and other neurodegenerative disorders is oxidative stress [3][4][5]. Due to the important antioxidant functions of CoQ 10 , several publications over the last two decades have addressed the issues of both determinations of CoQ 10 levels in different tissues of patients diagnosed with AD or other types of dementia and on the potential therapeutic role of CoQ 10 in these diseases (considering experimental studies in animal models of dementia in humans suffering from AD or other dementias). This systematic review and meta-analysis aims to analyze the results of studies addressing the tissular concentrations of CoQ 10 in patients diagnosed with AD and other dementia syndromes compared with healthy controls, and the results of therapeutic trials of CoQ 10 in AD (including experimental models of this disease) and in other causes of dementia.

Search Strategy and Criteria for Eligibility of Studies
We undertook a literature search using 3 well-known databases (PubMed, EMBASE, Web of Science-WOS-Main Collection) from 1966 until 31 December 2022. We crossed the term "coenzyme Q10" with "Alzheimer's disease" (188, 403, and 171 items found in Pub-Med, EMBASE, and WOS, respectively), "dementia" (222, 79, and 86 items found in Pub-Med, EMBASE, and WOS, respectively), "vascular dementia" (13,9, and 8 items found in PubMed, EMBASE, and WOS, respectively), "Lewy body dementia" (9,8, and 11 items found in PubMed, EMBASE, and WOS, respectively) "Lewy body disease" (9,15, and 25 items found in PubMed, EMBASE, and WOS, respectively), and "mild cognitive impairment" (68,19, and 34 items found in PubMed, EMBASE, and WOS, respectively). The search retrieved 477 references which were examined one by one by the authors in order to select exclusively those strictly related to the proposed topic. Duplicated articles and abstracts were excluded. We did not apply any language restrictions. Figure 1 represents the flowcharts for the selection of eligible studies which analyzed tissue CoQ10 concentrations in patients with different types of dementia, and therapeutic trials with CoQ10 in experimental models of dementia or in patients with AD or other dementias according to the PRISMA guidelines [6].

Selection of Studies and Methodology for the Meta-Analyses
We performed a meta-analysis of observational eligible studies assessing the concentrations of CoQ10 in tissues of patients diagnosed with AD and/or other causes of dementia

Selection of Studies and Methodology for the Meta-Analyses
We performed a meta-analysis of observational eligible studies assessing the concentrations of CoQ 10 in tissues of patients diagnosed with AD and/or other causes of dementia and in controls. We extracted the following information: first author, year of publication, country, study design, and quantitative measures. We analyzed the risk for bias with the Newcastle-Ottawa Scale [7]. Table 1 summarizes data from selected studies analyzing tissular concentrations of CoQ 10 in patients diagnosed with AD, Lewy body dementia (LBD), vascular dementia (VD), and dementia without specification of etiology compared with controls (with the exception of one study that compares the serum/plasma CoQ 10 of patients with dementia with reference values). We converted plasma/serum and CSF CoQ 10 concentrations to nmol/mL when necessary. The meta-analyses were carried out using the R software package meta [16] and following both the PRISMA [6] (Table S1) and the MOOSE guidelines [17] (Table S2). Because of the high heterogeneity across studies, we applied the random-effects model and used the inverse variance method for the meta-analytical procedure, the DerSimonian-Laird as an estimator for Tau 2 [18], the Jackson method for the confidence interval of tau 2 and tau [19], and the Hedges' g (bias-corrected standardized mean difference) [20]. The statistical power to detect differences in mean values (alpha = 0.05) for the pooled samples was calculated when stated in the text. The meta-analysis was finally only applicable to three studies on serum/plasma CoQ 10 concentrations in patients with AD compared with controls.

Alzheimer's Disease
A total of three studies that assessed the serum/plasma levels of CoQ 10 in patients with AD and controls failed to detect significant differences between the two study groups (Table 1, Figure 2) [8][9][10]. One of these studies showed a similar serum/plasma CoQ 10 /cholesterol ratio between AD patients and controls [8].
Antioxidants 2023, 12, x FOR PEER REVIEW 4 following both the PRISMA [6] (Table S1) and the MOOSE guidelines [17] (Table S2) cause of the high heterogeneity across studies, we applied the random-effects model used the inverse variance method for the meta-analytical procedure, the DerSimon Laird as an estimator for Tau 2 [18], the Jackson method for the confidence interval of and tau [19], and the Hedges' g (bias-corrected standardized mean difference) [20]. statistical power to detect differences in mean values (alpha = 0.05) for the pooled sam was calculated when stated in the text. The meta-analysis was finally only applicab three studies on serum/plasma CoQ10 concentrations in patients with AD compared controls.

Alzheimer's Disease
A total of three studies that assessed the serum/plasma levels of CoQ10 in pat with AD and controls failed to detect significant differences between the two study gr (Table 1, Figure 2) [8][9][10]. One of these studies showed a similar serum/plasma CoQ10/ lesterol ratio between AD patients and controls [8]. Isobe et al. [11,12] reported increased total CoQ10 and oxidized CoQ10 concentra in the cerebrospinal fluid from AD patients compared with controls, and a negative relation between oxidized/total coenzyme Q10 and duration of the disease.
To date, only two studies have addressed brain CoQ10 concentrations in patients AD. Edlund et al. [21] described the mean values (without SD) of CoQ10 in frontal, pre tral, temporal, and occipital cortex, and in nucleus caudate, hippocampus, pons, cer lum, and medulla oblongata of AD patients and controls. They reported a 30-100 % crease in CoQ10 concentrations in most of these regions; however, the number of AD tients and controls involved in the study was not stated. Kim et al. [22] described a creased activity of the 25 kDa subunit nicotinamide adenine dinucleotide + hydr (NADH):ubiquinone oxidoreductase (complex I) in the temporal and occipital cortex of the 75 kDa subunit of this enzyme in the parietal cortex of patients with AD comp with controls, but specific measures of CoQ10 were not performed.
Santa-Mara et al. [23] reported the presence of CoQ10 in paired helical filaments errant protein aggregates containing tau protein) and in Hirano bodies (neuronal in sions that are mainly observed in hippocampal neurons and are composed of actin e associated with or not associated with tau) in brain patients with AD, and state that C was able to induce the formation of aggregates when it was mixed with tau and actin Isobe et al. [11,12] reported increased total CoQ 10 and oxidized CoQ 10 concentrations in the cerebrospinal fluid from AD patients compared with controls, and a negative correlation between oxidized/total coenzyme Q 10 and duration of the disease.
To date, only two studies have addressed brain CoQ 10 concentrations in patients with AD. Edlund et al. [21] described the mean values (without SD) of CoQ 10 in frontal, precentral, temporal, and occipital cortex, and in nucleus caudate, hippocampus, pons, cerebellum, and medulla oblongata of AD patients and controls. They reported a 30-100% increase in CoQ 10 concentrations in most of these regions; however, the number of AD patients and controls involved in the study was not stated. Kim et al. [22] described a decreased activity of the 25 kDa subunit nicotinamide adenine dinucleotide + hydrogen (NADH):ubiquinone oxidoreductase (complex I) in the temporal and occipital cortex and of the 75 kDa subunit of this enzyme in the parietal cortex of patients with AD compared with controls, but specific measures of CoQ 10 were not performed.
Santa-Mara et al. [23] reported the presence of CoQ 10 in paired helical filaments (aberrant protein aggregates containing tau protein) and in Hirano bodies (neuronal inclusions that are mainly observed in hippocampal neurons and are composed of actin either associated with or not associated with tau) in brain patients with AD, and state that CoQ 10 was able to induce the formation of aggregates when it was mixed with tau and actin.

Other Causes of Dementia
Serum CoQ 10 concentrations and CoQ 10 /cholesterol ratios from patients diagnosed with LBD [13] and VD [8] did not differ significantly from those of controls according to two single studies.
Yamagishi et al. [14], in a community-based cohort study in Japan involving 6000 Japanese participants aged 40-69 years at baseline, described an inverse association between serum CoQ 10 concentrations and the risk for disabling dementia, although serum CoQ 10 levels and serum CoQ 10 /cholesterol ratio did not differ significantly between 65 incident cases and 130 controls.

Studies Assessing Therapeutic Response to CoQ 10 Administration in Experimental Models of AD and Other Dementias
The results of studies assessing the response to the administration of COQ 10 in different experimental models are summarized in Table 2. Coadministration of CoQ 10 and alpha-tocopherol (but not administration of each of these compounds alone) improved learning and memory tasks (assessed by a test that required the mice to rapidly identify and remember the correct arm of a T-maze, and to respond preemptively in order to avoid an electric shock).

AGED MICE Wadsworth et al., 2008 [25]
Administration of CoQ 10 decreased protein carbonyls in the brain but had no effect on lipid peroxidation, brain ATP levels, and mitochondrial membrane potential.

Sumien et al., 2009 [26]
Intake of a low-CoQ 10 diet did not change age-associated decrements in muscle strength, balance, coordinated running, or learning/memory, whereas intake of CoQ 10 at a higher amount increased spontaneous activity, worsened age-related losses in acuity to auditory and shock stimuli, and impaired spatial learning/memory of old mice.

Shetty et al., 2013 [27]
Intake of a low-CoQ 10 diet did not change age-associated decrements in tests for spatial learning (Morris water maze), spontaneous locomotor activity, motor coordination, and startle reflex. However, intake of high-CoQ 10 improved spatial learning and decreased protein oxidative damage in the heart, liver, skeletal muscle, and to a lesser extent, in the brain mitochondria.
Shetty et al., 2014 [28] Administration of α-tocopherol or α-tocopherol + CoQ 10 diets improved coordinated running performance. The α -tocopherol + CoQ 10 diet improved performance in a discriminated avoidance task (α-tocopherol and CoQ 10 diets alone improved this task to a lesser degree). Both α-tocopherol and CoQ 10 diets decreased protein damage, this effect being more marked with the α-tocopherol + CoQ 10 combination.

HYPERCHOLESTE-ROLEMIA-INDUCED AD IN RATS
Ibrahim Fouad, 2020 [29] Treatment with omega-3 and CoQ 10 alone or in combination decreased markers of brain oxidative stress and inflammation and serum Aβ levels, regulated cholinergic functioning, and enhanced the functional outcome.
Attia et al., 2020 [31] Treatment with CoQ 10 alone or in combination with biotin attenuated the changes induced by AlCl3 (impaired memory, a significant increase in Aβ, lipid peroxides, inflammatory markers-TNFα, IL6, IL1, nuclear factor κB-, caspase-3, and pSer-IRS-1, significant reduction in the antioxidants reduced glutathione and SOD-, pTyr-IRS-1, and p-Akt, reflecting Aβ-induced inflammation and defective insulin signaling, focal aggregations of inflammatory cells and neuronal degeneration). Administration of CoQ 10 to forebrain lesioned rats caused an increase in nerve growth factor (NGF) protein and mRNA and in choline acetyltransferase activity, and improved memory tasks such as behavioral deficits in habituation, water maze, and passive avoidance tasks in these animals. Administration of CoQ10-loaded exosomes derived from adipose-derived stem cells improved memory impairment (assessed with the Morris water maze and passive avoidance task), increased BDNF expression, and increased cell density and the transcription factor SOX2 gene expression in comparison with the administration of CoQ 10 exosomes derived from adipose-derived stem cells alone. CoQ 10 administration improved cognitive performance during Morris water maze testing, decreased brain levels of protein carbonyls (a marker of oxidative stress), decreased brain Aβ42 levels and Aβ protein precursor (AβPP), β-carboxyterminal fragments, and decreased plaque area and number in the hippocampus and the overlying cortex (assessed by immunostained with an Aβ42-specific antibody). Administration of ubisol-Q 10 (a water-soluble form of coenzyme Q 10 ) improved long-term memory, preserved working spatial memory, and inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. The administration of CoQ 10 altered changes in the differentially expressed serum proteins in the transgenic compared with wild-type mice by up-regulating 10 proteins and down-regulating another 10 proteins. Among the proteins modulated by CoQ10, clusterin and α-2-macroglobulin were validated via ELISA assay. CoQ 10 treatment decreased reactive oxygen species generation, increased population doublings, and postponed stress-induced premature senescence. CoQ 10 treatment increased proliferating cell nuclear antigen expression, and decreased levels of manganese-SOD (MnSOD), p21, p16Ink4A and cell cycle regulatory protein retinoblastoma (suggesting a resumption of autophagy).

Vegh et al., 2019 [46]
Administration of ubisol-Q 10 caused enhanced expression autophagy-related genes such as beclin-1 (a major autophagy regulator) and mitogen-activated protein kinase 8 (MAPK8/JNK1, a major activator of beclin-1) avoiding resumption of premature senescence. Withdrawal of ubisol-Q10 treatment led to the return of the senescence phenotype in AD fibroblasts. Exposure of these cells to Aβ(1-42) caused, among other effects, enhanced lipid peroxidation and protein oxidation and significant reductions in the total contents of phospholipids, ubiquinone-10, and alpha3 and alpha7 subunit proteins of nicotinic acetylcholine receptors. Co-administration of CoQ 10 restored the Aβ(25-35) oligomer-inhibited proliferation of neural stem cells by increasing the expression levels of proteins related to the PI3K pathway (p85α PI3K, phosphorylated Akt-Ser473-, phosphorylated glycogen synthase kinase-3β-Ser9-, and heat shock transcription factor). This protective effect was blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor.  In general, the administration of CoQ 10 alone or in combination with other substances (mainly other antioxidants) has been useful to improve the results of clinical tasks related to learning and memory and to improve or prevent oxidative stress, inflammation and cellular death in different models of AD and frontotemporal dementia including aged rodents [24][25][26][27][28][29], aluminium-induced AD in rats [30][31][32], forebrain lesioned rats [33], intracerebroventricular infusion of Aβ-42 [34] or streptozotocin [37,38] or intrahippocampal injection of Aβ-42 [35,36] in rats, transgenic mice with different mutations inducing AD [39][40][41][43][44][45][46] or frontotemporal dementia [42], and cell cultures using different human [25,45,46,48] or rodent cells [49][50][51][52][53][54][55]. On the other hand, Aβ(1-42) decreased CoQ 10 concentrations in human SH-SY5Y neuroblastoma cells in culture [47]. Table 3 summarizes the results of the eight eligible studies addressing the therapeutic response to CoQ 10 administration in patients with AD [56][57][58][59][60][61][62][63], although in one of them, an important percentage of patients included were diagnosed with mixed dementia [61]. Two of these studies used an open-label design [56,61] while the others were randomized clinical trials [33].    Imagawa et al. [56], after a preliminary report indicating that therapy with CoQ10, iron, and vitamin B6 was effective as mitochondrial activation therapy in 27 AD patients, reported a significant clinical improvement with this therapy in two genetically confirmed AD patients. Three of the randomized clinical trials showed improvement in neuropsychological assessments in patients treated with CoQ 10 compared, respectively, with placebo [57,58] or with tacrine [59], while the other two did not show any improvement in comparison with placebo [60,62], although in one of them, the patients treated with CoQ 10 showed a better outcome than those treated with a combination of α-tocopherol, vitamin C, and α-lipoic acid [62].

Alzheimer's Disease
Karakahya and Özcan [63], in a study using optic coherence tomography (OCT), reported an improvement in retinal ganglion cell loss related to AD with short-term topical administration of CoQ10. Finally, an open-label study showed some degree of improvement in the MMSE score and other neuropsychological tests in patients with AD or mixed dementia [61].
Qi et al. [65], in a randomized clinical trial involving 88 patients diagnosed with VD (44 of them assigned to treatment with butylphthalide plus idebenone as the observational group, and 44 to idebenone as the control group), showed a higher degree of improvement in MMSE, clinical dementia rating scale (CDRS), and ability of daily life (ADL), and a higher decrease in serum IL6, C reactive protein, TNFα, IL1β, CD31+, CDl44+, and endothelin-1 levels in the observational group compared with the control group.

Mild Cognitive Impairment and Normal Aging
García-Carpintero et al. [66], in a 1-year randomized, double-blind, placebo-controlled observational analytical study involving 69 patients diagnosed with mild cognitive impairment (MCI) assigned to CoQ 10 200 mg/day (n = 33) or placebo (n = 36) showed that although CoQ 10 treatment improved cerebral vasoreactivity (assessed by transcranial Doppler sonography) and inflammatory markers, it did not display any significant improvement in the results of an extensive neuropsychological assessment.
Finally, Stough et al. [67] designed a 90-day randomized, double-blind, placebocontrolled, parallel group clinical trial involving 104 healthy subjects aged 60 years and over randomized to either CoQ 10 200 mg/day or placebo (52 per group), aiming to evaluate the effects of CoQ 10 in the amelioration of cognitive decline that it should be undergoing. Interestingly, a recent study described a significant association of plasma CoQ 10 concentrations with cognitive functioning and executive function in elderly people [68].

Discussion and Conclusions
The possible role of CoQ 10 in the pathogenesis of AD and other causes of dementia, if any, is far from established with the current evidence. The studies addressing the serum/plasma levels of CoQ 10 , which are scarce and based on a relatively small sample size, were similar for AD patients and controls [8][9][10]. The increased values of total and oxidized CoQ 10 concentrations in the cerebrospinal fluid from patients [11,12] and in certain brain areas from patients with AD [13], described in single studies, have not had further replication studies and await confirmation. Studies on human AD brain are restricted to a single report of a 30-100% increase in CoQ 10 concentrations in most of the regions studied (which included the frontal, precentral, temporal and occipital cortex, nucleus caudate, hippocampus, pons, cerebellum, and medulla oblongata) in an unspecified number of AD patients compared with controls [18]. The possibility of induction of aggregates of tau protein and actine by CoQ 10 and the finding of the presence of this coenzyme in paired helical filaments and Hirano bodies in the hippocampus [23] lends support to the hypothesis of the possible role of CoQ 10 in AD. Studies reporting on CoQ 10 concentrations in other causes of dementia are restricted to the measurements in serum/plasma from patients with Lewy body dementia (LBD) [13], vascular dementia [8], and dementia without specification of etiologic diagnosis [14,15].
Because of their antioxidant actions, it was proposed that CoQ 10 administration could be a potential protective therapy in AD [69,70]. Moreover, an important number of studies have shown a significant neuroprotective and/or clinical effect of the administration of CoQ 10 in different experimental models of AD, as was previously commented in more detail in the Section 3 [49][50][51][52][53][54][55] (Table 2). Interestingly, most of the studies performed using cell cultures including human neuroblastoma SH-SY5Y [47] and human MC 65 neuroblastoma cells [25], human umbilical vein endothelial cells [48], rat endothelial [49], cortical [50,51] and brain stem cells [52], hippocampal neurons from fetal mice [53], brain mitochondria isolated from aged diabetic rats [54], and rat pheochromocytoma (PC12) cells [55] have shown a protective effect of CoQ 10 on the neurotoxic effects of different types of Aβ. In addition, it has been shown that oral administration of CoQ 10 results in an important increase in serum/plasma CoQ 10 concentrations in humans [71][72][73] and in rats [73].
The potential beneficial effects of CoQ 10 administration, its good absorption, and the lack of important adverse effects led to some initial short-term randomized clinical trials that showed improvement in several neuropsychological tests in patients with AD treated with CoQ 10 in comparison with those assigned to placebo [57,58] or the anticholinesterase drug tacrine [59]. However, a further short-term randomized clinical trial failed to determine any benefit except a mild improvement in the ADAS-Cog scores [60].
In conclusion, according to the data from the results presented in this review, there are still important knowledge gaps regarding both the suitability of CoQ 10 as a biomarker of AD and other causes of dementia (studies on this issue in brain, cerebrospinal fluid, and other tissues are scarce) and the possible usefulness of treatment with CoQ 10 in patients with AD (controversial results of randomized controlled trials with a maximum of 1 year of follow-up) despite the promising neuroprotective effects of CoQ 10 detected in different models of AD. The design of further studies with a longer-term follow-up period is needed.